Metabolic inflammation is associated with obesity-induced insulin resistance, a chronic inflammatory condition mediated by activated tissue-resident macrophages. These cells accumulate in the liver, skeletal muscle and adipose tissue, where they secrete proinflammatory mediators and cause tissue dysfunction. Macrophage activation and function are under robust transcriptional control, and therefore a detailed understanding of the molecular mechanisms governing these processes is of critical importance. Studies in this proposal investigate the role of KLF2, a novel transcription factor, in modulating metabolic inflammation in vivo. KLF2 is a member of the Kruppel-like family of zinc-finger transcription factors and is known to regulate macrophage differentiation and function. However, a specific role for KLF2 in mediating metabolic inflammation has not been reported. Preliminary results demonstrate that animals specifically lacking Klf2 in the myeloid lineage (Mac-KLF2[Delta/Delta]) accelerated obesity and insulin resistance when animals are placed on a high-fat diet. Animals lacking myeloid- KLF2 develop an accumulation of macrophages in the stromal vascular fraction of visceral adipose tissue, and these macrophages express high levels of pro-inflammatory factors such as TNFalpha, IL-6, and macrophage chemoattractant protein-1 (MCP-1). Furthermore, crossing Mac-KLF2[Delta/Delta] to ApoE[-/-] confers an enhanced susceptibility to experimental atherosclerosis in response to a high fat diet. Finally, KLF2 inhibits the transcriptional activity of NFkappaB and AP-1, two central pro-inflammatory pathways which converge on numerous macrophage gene targets. These observations underlie the central hypothesis of this application that macrophage KLF2 regulates metabolic inflammation via repressive effects on NFkappaB and AP-1 signaling. The goals of this proposal are: (1) To determine if altering myeloid-specific KLF2 expression affects the development of metabolic inflammation in vivo, and (2) To determine the molecular mechanisms by which KLF2 expression regulates inflammatory macrophage activation. Collectively, these results will provide molecular, cellular, and in vivo insights regarding the role of KLF2 as a modulator of metabolic inflammation.